encorafenib and Neoplasm-Metastasis

Encorafenib (Braftovi

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Drug Interactions; Humans; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Sulfonamides; Survival Analysis

BRAF V600E mutations are associated with 8-10% of metastatic colorectal cancers (mCRC) and carry a poor prognosis with limited therapeutic options. In contrast to metastatic melanoma, BRAF inhibition alone or in combination with mitogen-activated protein kinase kinase (MEK) inhibitors has shown little utility in the treatment of BRAF V600E-mutant mCRC. This is secondary to upstream activation of the epidermal growth factor receptor (EGFR) pathway and other escape mechanisms. Combining RAF and MEK inhibitors with inhibition of the EGFR pathway through an anti-EGFR receptor antibody (cetuximab) led to the BEACON clinical trial (binimetinib, encorafenib and cetuximab). Trial patients had undergone at least one prior line of chemotherapy. The trial met all its endpoints and is now included in NCCN (National Comprehensive Cancer Network) guidelines. Herein we provide updates in treatment options for patients with BRAF V600E-mutant mCRC, focusing on the practice-changing BEACON-triplet regimen, the first chemotherapy-free combination regimen for mCRC. This combination is being explored frontline in the ANCHOR clinical trial.

Topics: Benzimidazoles; Carbamates; Cetuximab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Therapy, Combination; Humans; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; Sulfonamides

Encorafenib (Braftovi™), a BRAF inhibitor, and binimetinib (Mektovi

Topics: Benzimidazoles; Carbamates; Drug Approval; Humans; MAP Kinase Kinase Kinases; Melanoma; Molecular Structure; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Treatment Outcome; United States

In this open-label, phase III trial, 665 patients with. Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR. In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins B-raf; Standard of Care; Sulfonamides; Survival Rate

The BEACON trial showed that combination therapy with encorafenib (BRAF inhibitor) and cetuximab (EGFR inhibitor) was associated with prolonged overall survival compared with standard chemotherapy in patients with metastatic BRAF variant colorectal cancer. However, the cost-effectiveness of using these agents in this clinical setting is unknown.. To create a cost-effectiveness model to compare doublet therapy (encorafenib plus cetuximab) with standard chemotherapy (cetuximab plus irinotecan or cetuximab plus folinic acid, fluorouracil, and irinotecan) in treating patients with metastatic BRAF variant colorectal cancer.. This economic evaluation constructed a Markov model to compare the lifetime cost and utility of doublet therapy and standard chemotherapy. Parametric survival modeling was used to extrapolate the effectiveness of each line of therapy from large clinical trials. One-way and probabilistic sensitivity analyses assessed the uncertainty in the model. Patients mirrored the cohorts in the BEACON trial: they had metastatic BRAF variant colorectal cancer and were followed up as they progressed through multiple lines of therapy, best supportive care, and death. Data collection and data analysis were performed from November 15, 2019, to July 14, 2020.. The main outcome was the incremental cost-effectiveness ratio, which was calculated using the cumulative cost and effectiveness in quality-adjusted life years (QALYs), of doublet therapy compared with standard chemotherapy.. The model patient cohort had a mean age of 61 years, and 53% of the patients were women, 66% had 1 previous line of therapy, and 8% had high microsatellite instability. Doublet therapy was associated with an improvement of 0.15 QALYs compared with standard chemotherapy. However, the incremental cost of doublet therapy was $78 233, leading to an incremental cost-effectiveness ratio of $523 374 per QALY gained. Concomitant decreases in the price of encorafenib and cetuximab are needed to achieve cost-effectiveness at a willingness-to-pay threshold of $150 000 per QALY gained.. This study found that doublet therapy for metastatic BRAF variant colorectal cancer was unlikely to be cost-effective under current pricing. Cost-effectiveness needs to be considered in clinical trial design, particularly when combining new therapies with non-cost-effective treatments that are coadministered without a fixed duration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Markov Chains; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; Quality-Adjusted Life Years; Sulfonamides

Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited.. A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety.. A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases.. Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Brain Neoplasms; Carbamates; Female; Humans; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides

More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.

Topics: Antineoplastic Agents; Benzimidazoles; Bevacizumab; CA-125 Antigen; Carbamates; Carboplatin; Cystadenocarcinoma, Serous; Disease Progression; Everolimus; Female; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; MAP Kinase Kinase 1; Medroxyprogesterone; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Oximes; Paclitaxel; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Recurrence; Sulfonamides; Tamoxifen; Treatment Outcome; Young Adult

Targeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients.. We analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues. The oligocentre cohort 1 included 83 patients whose tumour tissues were analysed retrospectively with the anti-PD-L1 antibody clone E1L3N. The multicentre cohort 2 included 58 patients whose tumour tissues were analysed prospectively within the framework of the "Registry of the Arbeitsgemeinschaft Dermatologische Onkologie" (ADOREG) and "Tissue Registry in Melanoma" (TRIM) project using the anti-PD-L1 antibody clone 28-8.. PD-L1 expression in pre-treatment tumour tissue did not correlate with response or survival to BRAFi-based therapies in both MM patient cohorts. This finding was not influenced by retrospective versus prospective immunohistochemistry analyses, oligocentre versus multicentre cohorts or the different anti-PD-L1 antibody clones used. In cohort 1, PD-L1 positivity was detected in tumour tissue of 41.0% and 18.1% of patients (cut-off 1% and 5%, respectively). In cohort 2, 58.6% and 39.7% of patients showed PD-L1 positivity (cut-off 1% and 5%, respectively).. In two independent cohorts including a total of 141 MM patients, PD-L1 expression in tumour tissue did not correlate with the outcome of BRAFi-based treatment. Therefore, PD-L1 cannot be recommended for the use as a predictive biomarker of BRAFi-based therapy in BRAF V600-mutated MM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carbamates; Female; Humans; Imidazoles; Indoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Retrospective Studies; Sulfonamides; Treatment Outcome; Vemurafenib; Young Adult

LGX818 is a new-generation BRAF inhibitor (BRAFi) that is currently undergoing phase 3 trials for the treatment of BRAF mutant metastatic melanoma patients (NCT01909453). Cutaneous toxicities associated with the administration of BRAF inhibitors are considered to be induced by the paradoxical activation of the mitogen-activated protein kinase pathway in wild-type BRAF cells. Changes in naevi, including new naevi, hyperpigmentation and fading of existing naevi, have also been reported. In addition, some patients receiving these therapies have developed second primary melanomas. As a consequence, the importance of sequential digital dermoscopy in all patients treated with a BRAFi to detect new primary melanomas has been emphasized. A 61-year-old man with BRAF mutant stage IV metastatic melanoma was commenced on the phase 1 trial of LGX818 at 300 mg daily in 2013. After 2 months of therapy, the patient was noted to have developed eruptive naevi, fading of existing naevi and darkening of other naevi. Excision of a new pigmented lesion from the back indicated a compound naevus. Immunohistochemistry showed that the naevus cells lacked a BRAF V600E mutation. This is the first reported case of eruptive naevi in a patient treated with LGX818. The absence of the BRAF V600E mutation within a changing naevus supports the theory that BRAFi stimulates the proliferation of wild-type BRAF cells. Close dermatological surveillance is important for all patients treated with any type of BRAFi.

Topics: Antineoplastic Agents; Carbamates; Dermatology; Dermoscopy; Humans; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Nevus, Pigmented; Pigmentation; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides